PROJECTSUMMARY Foodallergies(FAs)areaworld-wideproblem,andallergiestomultiplefoodsareparticularlyproblematic.In theU.S.,ingestionofoffendingfoodallergensisthemostcommoncauseofanaphylaxisseeninhospital emergencydepartments(EDs),anditisestimatedthat~30,000food-inducedanaphylacticeventsareseenin U.S.EDseachyear;?sadly,~200oftheseeventsprovefatal.Peanutsortreenutscausethemajorityofthese deaths,andarecentsurveyintheU.S.foundthat1.4%ofthepopulationisallergictopeanutsortreenutsand ~30%ofpatientswithFAshaveallergiestomultiplefoods.Inpeanutallergy(PA),landmarkstudiesbyA. WesleyBurksandcolleagueshaveshownthatchildrencanbedesensitizedtopeanutviaanoral immunotherapy(OIT)protocol.Wehavereplicatedtheseresultsinadultsandchildren,andalsohavecarried outapilotstudyshowingthatFApatientscanbedesensitizedtomultiplefoodallergenssimultaneously(i.e., multi-OIT).Moreover,wefoundthattherewerefeweradverseeventsinthebuild-upphaseofmulti-OITif patientsreceivedtheanti-IgEantibody,omalizumab,concomitantlywithmulti-OIT. Inanefforttoimproveunderstandingofthesystemicandlocal(i.e.,GI)immuneresponsesthatunderliePA andtherapeuticresponsestoOIT,wearecurrentlyconductingaplacebo-controlled,randomized,phase2 clinicaltrialofOITin120childrenandadultswithPA(thePOISEDtrial),andareapplyingstate-of-the-art humanimmunemonitoringmethodstoanalyzebloodandGItissuespecimensofparticipantsinthatstudy.In thisAADCRCU19renewalapplication,weproposetoconductapilot,placebo-controlled,randomized,phase 2clinicaltrialofOITwithorwithoutomalizumabortheanti-IL-4R?antibody,dupilumab,inchildrenandadults withmultipleFAs(multi-FAs).WeproposetomeasureabroadrangeofbloodandGIbiopsycellularfindings, aswellasserologicandclinicalfindings,inlongitudinalsamplesfrommulti-FAparticipantsundergoingthetrial, aswellasfromappropriatecontrolparticipants(i.e.,multi-FAparticipantswhoarenottreated,healthycontrols, andatopiccontrolswithoutFA).WewillusethesedatatodefinehowkeysystemicorGItissueimmune parameterschangeduringmulti-OIT,andwhicharemostpredictiveofthenatureanddurabilityofpatient responsestothistherapy.Specifically,wewillevaluatewhetherthereareblood-orGItissue-derived biomarkersthatpredicttherapeuticresponsestoindividualallergens,ortoallallergens,inmulti-OIT.In addition,wewillseektoidentifyimmunemonitoringparameters,includingfindingsderivedfromanalysesof basophilphenotypeandfunctionthatcanberapidlyperformedinaclinicallaboratoryusingsmallamountsof blood,thatcouldbeusedtopredicttheclinicalreactivitytooffendingallergensinmulti-FAsubjects,toimprove thesafetyandefficacyofOITprotocols,and/ortotailortheOITprotocoltoeachindividualsubject.